Hemochromatosis is characterized by a chronic increase in intestinal iron absorption, leading to excessive iron deposition in the liver, heart, pancreas and other organs. Patients who are homozygous for mutations in the HFE gene or heterozygous for mutations in the FPN gene are at risk for these complications, but there is variability in disease severity. This has been particularly well studied for HFE hemochromatosis; some individuals have severe complications in the third decade of life, whereas others reach old age with little or no evidence of iron toxicity. The severity of the disease correlates with the extent of tissue iron loading. The goal of this proposal is to identify genes that modify iron-loading phenotypes. This will be done using mice, because mice are similar to humans in their iron metabolism, and mouse models of both HFE hemochromatosis and FPN hemochromatosis are available in the laboratory. Preliminary studies show that two inbred mouse strains, C57BL/10 and SWR, differ markedly in their tissue iron loading phenotypes. C57BL/10 mice accumulate little iron in the liver and spleen, while SWR mice accumulate large iron burdens in both tissues. Quantitative liver and spleen iron loading data were used in a quantitative trait locus (QTL) analysis to identify chromosomal regions that have a high probability of accounting for differences in iron loading between the two strains. In the analysis of 96 N2 backcross animals from a cross between these strains, at least 4 QTLs (LOD scores 2.9 - 4.0) were identified for liver iron loading, and one QTL (LOD 8.3) was identified for spleen iron loading. The aims described in this proposal are (1) to identify the genes responsible for these QTLs, and (2) to determine whether these and other potential modifiers of iron loading also modify the phenotypes of mice with Hfe and Fpn hemochromatosis.